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Sam68-Like Mammalian Protein 2, Identified by Digital Differential Display as Expressed by Podocytes, Is Induced in Proteinuria and Involved in Splice Site Selection of Vascular Endothelial Growth Factor

Clemens D. Cohen^*, Peter P. Doran, Simone M. Blattner^*, Monika Merkle^*, Guo Q. Wang, Holger Schmid^*, Peter W. Mathieson, Moin A. Saleem, Anna Henger^*, Maria P. Rastaldi and Matthias Kretzler^*

^* Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany; Department of Medicine and Therapeutics, University College, Dublin, Ireland; Renal Immunopathology Laboratory, San Carlo Borromeo Hospital, Milan, Italy; and Children’s Renal Unit and Academic Renal Unit, University of Bristol, Bristol, United Kingdom

Address correspondence to: Dr. Clemens D. Cohen, Medizinische Poliklinik, Ludwig-Maximilians-University, Pettenkoferstrasse 8A, Munich, 80336, Germany. Phone: +49-89-2180-75841; Fax: +49-89-2180-75860; E-mail: ccohen{at}med.uni-muenchen.de

Received for publication February 22, 2005. Accepted for publication March 10, 2005.

Podocytes, the glomerular epithelial cells of the kidney, share important features with neuronal cells. In addition to phenotypical and functional similarities, a number of gene products have been found to be expressed exclusively or predominantly by both cell types. With the hypothesis of a common transcriptome shared by podocytes and neurons, digital differential display was used to identify novel podocyte-expressed gene products. Comparison of brain and kidney cDNA libraries with those of other organs identified Sam68-like mammalian protein 2 (SLM-2), a member of the STAR family of RNA processing proteins, as expressed by podocytes. SLM-2 expression was found to be restricted in the kidney to podocytes. In proteinuric diseases, SLM-2, a known regulator of neuronal mRNA splice site selection, was found significantly upregulated on mRNA and protein levels. Knockdown of SLM-2 by short interfering RNA in podocytes was performed to evaluate its biologic role. RNA splicing of vascular endothelial growth factor (VEGF), a key regulator of the filtration barrier and expressed as functionally distinct splice isoforms, was evaluated. VEGF₁₆₅ expression was found to be reduced by 25% after SLM-2 knockdown. In vivo, the glomerular expression of SLM-2 correlated with the mRNA levels of VEGF₁₆₅. This study demonstrates the power of digital differential display to predict cell type–specific gene expression by hypothesis-driven analysis of tissue cDNA libraries. SLM-2-dependent VEGF splicing indicates the importance of mRNA splice site selection for glomerular filtration barrier function.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673